A Sigh of Relief for Painkillers

< Opiates are powerful painkillers, but they come with some baggage: a troubling tendency to depress breathing. By giving an experimental drug along with a narcotic, a team of researchers has eliminated the opiate's potentially lethal side effect while preserving its ability to blunt pain. The result could have far-reaching clinical implications for anesthesia and the treatment of acute and chronic pain.

Like morphine and other narcotics, a painkiller called fentanyl disrupts nerve cells deep in the brain that register pain as well as other cells that govern breathing rhythm. Well-controlled doses of the drug can work wonders, but overexposure can be disastrous: In October 2002, 129 people died in a Moscow theater when authorities subdued hostage-takers there by pumping what many believe was fentanyl into the building.

Even before the hostage crisis, physiologist Diethelm Richter and his colleagues at the University of Göttingen, Germany, were wondering whether fentanyl's effects on breathing and pain could be separated. The group examined a small chunk of rodent brainstem called the pre-Bötzinger complex (PBC), which regulates breathing. Many cells in the PBC contain a receptor called 5-HT4(a). All these receptor-bearing cells in the PBC, the scientists found, also sport the -opioid receptors that react to the drugs. That makes sense, given that opiates can depress breathing. The finding also raised the prospect of controlling pain without disturbing breathing.

To see if their hunch was on target, the scientists dosed rats with so much fentanyl that they needed to be put on ventilators. Then Richter's group added an experimental drug that activates 5-HT4(a). The animals' breathing returned to roughly 80% of normal. And fentanyl remained so effective that the rats didn't flick their tails away from a hot lamp, they report in the 11 June issue of Science. They suggest that even though fentanyl may no longer bind to opioid receptors in the PBC, narcotic-sensitive brain cells outside the PBC are enough to deaden pain.

"It was idealism, if you like, wondering whether or not these processes could be untangled," says Julian Paton, a physiologist at the University of Bristol, U.K., who was not involved in the research. The success, he says, is "spectacular." But the 5-HT4(a) activators are far from ready for use in humans. For one, scientists don't know what the receptors control aside from breathing, so the side effects of enhancing them are uncertain, says Patrice Guyenet, a neuropharmacologist at the University of Virginia in Charlottesville.